Sequential activation of ERK and repression of JNK by scatter factor/hepatocyte growth factor in Madin-Darby canine kidney epithelial cells

The scattering of Madin-Darby canine kidney (MDCK) epithelial cells by scat ter factor/hepatocyte growth factor (SF/HGF) is associated with transcripti onal induction of the urokinase gene, which occurs essentially through acti vation of an EBS/AP1 response element. We have investigated the signal tran sduction pathways leading to this transcriptional response. We found that S F/HGF induces rapid and sustained phosphorylation of the extracellular sign al-regulated kinase (ERK) MAPK while stimulating weakly and then repressing phosphorylation of the JUN N-terminal kinase (JNK) MAPK for several hours. This delayed repression of JNK was preceded by phosphorylation of the MKP2 phosphatase, and both MKP2 induction and JNK dephosphorylation were under the control of MEK, the upstream kinase of ERK. ERK and MKP2 stimulate the EBS/AP1-dependent transcriptional response to SF/HGF, but not JNK, which in hibits this response. We further demonstrated that depending on cell densit y, the RAS-ERK-MKP2 pathway controls this transrepressing effect of JNK. To gether, these data demonstrate that in a sequential manner SF/HGF activates ERK and MKP2, which in turn dephosphorylates JNK. This sequence of events provides a model for efficient cell scattering by SF/HGF at low cell densit y.